We have identified a unique signature for DNA polymerase zeta which is to generate tandem mutations druing somatic hypermutation. Using mice deficient for various polymerases, we observed that polymerase eta is a dominant protein, and the effect of polymerase zeta was more pronounced in the absence of polymerase eta. Furthermore, data sugest that polymerase zeta functions in the MSH2-MSH6 pathway. An advantage to using polymerase zeta to inroduce tandem mutations would be to efficiently change amino acids in variable genes to generate higher affinity antibodies.